Solid Dosage Form That Promotes Reliable Oral, Esophageal and GI Transit

ABSTRACT

A solid dosage form designed to facilitate rapid and reliable oral, esophageal and GI transit has a surface area of the contact patch, i.e., the area of contact between the dosage form and the bodily surface reduced. The dosage form can be an asymmetric oral dosage unit containing a bioactive, the dosage unit being asymmetric with respect to a rotational axis perpendicular to a longitudinal axis of the dosage form, the rotational axis being located substantially at a mid point along the longitudinal axis. The dosage unit may have an outer surface ridged or dimpled or have at least one annular ring so as to reduce the contact patch of the dosage unit with a flat surface compared to non-ridged dosage unit of the same size and shape. The oral dosage unit can also have a spherical shape with or without ridges and/or dimples. Dies for forming these oral dosage units have, in a closed state, a cavity having a shape corresponding to the oral dosage unit.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of Ser. No. 13/759,138filed Feb. 5, 2013, which is a divisional of application Ser. No.13/079,285, filed Apr. 4, 2011, now U.S. Pat. No. 8,383,135, which is acontinuation-in-part of application Ser. No. 12/960,192, filed Dec. 3,2010, the contents of each of which are incorporated herein byreference.

BACKGROUND

The swallowing of oral medications has long been understood to beproblematic for large segments of the population. As many as one thirdof the United States patient population perceives difficulty inswallowing tablets, capsules, caplets and liquigels. Such difficultiesare particularly acute for dysphagics, cancer patents, the elderly,children and other groups (for a good primer on causes of swallowingdifficulties, see the Mayo Clinic's online treatment of the issue.

The issue of difficulty with swallowing oral medications involvesseveral problems. One problematic group is the case of a physiologically“normal” patient who perceives difficulties or discomfort in swallowingsolid oral medications. Such patients commonly fail to take theirmedications in a compliant manner. They may not take their medicationswhen recommended, if at all. Frequently, they will crush their tablets,which may defeat time release systems or otherwise adversely alter thedesired pharmacokinetic performance of the drug.

The most immediately severe swallowing problem is Actual EsophagealTransit Failure (AETF)—where the tablet actually becomes lodged orsticks in the esophagus. Such failure is generally understood to occurwhere transit takes thirty seconds or greater but in many cases thetransit failure can be total until dissolution. Apart from the failureto deliver the intended medication, many classes of drugs are corrosiveto the esophagus. While bisphosphonates, like Fosamax® are commonlyunderstood by practitioners to pose a threat to the esophagus, themedical literature demonstrates that there many classes of drugs thatpose a danger—over seventy drugs have been reported to cause esophagealdisorders (including inter alia, anti bacterials like doxycycline,tetracycline, clindamycin, etc (see D. Jaspersen, “Drug-inducedoesphageal disorders: pathogenesis, incidence, prevention andmanagement,” Drug Saf. 2000; March; 22(3): 237-49)). The typicalpractitioner is not always familiar with this literature, or simply doesnot have the knowledge or tools to remedy the issue.

A further problem is posed by the effect of delayed esophageal transiton the timing of peak drug concentration—effective blood levels can bematerially delayed by common place transit failure. In a study of twentypatients awaiting cardiac catheterization, 11 patients took anacetaminophen tablet while supine. Transit was delayed in ten of theseeleven subjects. The authors observed: “when there was delayedesophageal transit of tablets, the initial absorption of acetaminophen(measured as AUC over the first 60 min) was lower than that after normalesophageal transit of tablets. The peak plasma acetaminophenconcentration was also lower and occurred 90 min later when transit wasdelayed. These kinetic changes decrease the effectiveness ofacetaminophen as an analgesic.” See K. S. Channer and C J Roberts,“Effect of Delayed Esophageal Transit on Acetaminophen Absorption”Clinical Pharmacology and Therapeutics 37, 72-76 (1 Jan. 1985).

To date, there have been two primary attempts to address this issue. Thefirst effort has been the invention of rapidly dissolving dosage formsthat dissolve in the mouth prior to esophageal transit, most prominentlyquick dissolve tablets. Various manufacturing methods have been taughtand commercialized, including, the Zydis® freeze dried tablet, CIMA'sOrasolv® effervescent tablet (now owned by Cephalon), FuiszTechnologies' Flashdose® shearform matrix (invented principally by oneof the inventors hereof, Richard C. Fuisz, M.D.), and others.Additionally, other quick dissolving dosage forms have been taught, suchas thin film (see the following issued patents on thin film by thecurrent inventors: Fuisz et al. U.S. Pat. Nos. 7,425,292, 7,500,984,7,666,332, 7,824,588 and 7,897,080)). Sheet and slab dosage forms areanother alternative (see e.g. Fuisz US 20100247612A1). Transdermal,vaginal, intra-nasal, buccal, inhalation, intraocular and other systemsbypass swallowing entirely. In practice, not all drugs will be suitablefor such alternative delivery forms as is manifest in the market shareof drug consumption by delivery site.

The second primary attempt to address swallowing difficulties of soliddosage forms has involved the introduction of a superior liquid, toeither replace or in some cases augment water during the administration.For example one of the present inventors teaches a liquid with enhancedrheological properties that replaces water during solid dosage formadministration and eases esophageal transit by enveloping the soliddosage form in boundary layers of liquid (see one of the currentinventor's Fuisz U.S. Pat. No. 6,337,083; see also, Baichwal et al. U.S.Pat. No. 5,670,169; Unger U.S. Pat. No. 6,134,276; RobertsonUS2007/068012; Fukui C A 2 538 755; and Dairiku et al. EP 0 0873 749).However, the commercial reality has been that companies have been slowto adopt the use of enhanced liquids with the additional distributionand costs issues implied thereby. The solid dosage form—administeredwith water—remains the gold standard of convenience and cost containmentfor the administration of most drugs.

The mechanics of esophageal transit for a conventional solid dosage form(e.g. a tablet) have been lightly studied but with provocativeimplications. For example, a study at the University of Berlindemonstrates that, when administering tablets with water, the volume ofwater and the position (erect being best) of the patent are key drivers:in the upright position, 45% of capsules were trapped in the oesophagusat a swallowing volume of 5 mL, 7% at 25 mL and 0% at 50 mL. In thesupine position, the retention rate was 54% at 5 mL, 28% at 25 mL and 4%at 50 mL (See “Oesophageal transport of solid dosage forms depends onbody position, swallowing volume and pharyngeal propulsion velocity,” E.Osmanoglou et al, Neurogastroenterol Motil (2004) 16, 547-556; See also,“Measurement of the Esophageal Transit Time Using a Magnetic Market”Cordova-Fraga et al, Eighth Mexican Symposium On Medical Physics). Thus,the primary finding of Osmanoglu et al. is that upright administrationwith a high volume of liquid promotes reliable transit. This finding isincorporated in the instructions that accompany bisphosphonates likeFosamax® and Actonel® wherein the patient is instructed to take thetablet with a large amount of water and then remain standing for onehour afterwards. Of course, upright administration with large volumes ofwater is not practical for many patient populations, and supine or semisupine administration is the reality for many care situations.Additionally, as the population ages, the compliant use of specificvolumes of water for swallowing becomes more problematic.

There is a limited body of literature that addresses the relative easeof swallowing of various, conventional solid dosage forms as comparedwith one another. See Hey et al (“Oesophageal transit of six commonlyused tablets and capsules” British Medical Journal Volume 285, Dec. 11,1982) (concluding that “small tablets are swallowed most easily,” andlarge tablets should be “oval and not round,” and “capsules of a highdensity are easier to swallow than lighter ones.”); Drake et al.(“Monitoring esophageal transit of wax-polished Alendronate in healthypostmenopausal women: a new technique for the study of pill transittime” Current Therapeutic Research, 2002 vol. 62 n 2, pp 103-109)(concluding that “oval wax-polished alendronate tablets pass through theesophagus rapidly”); Perkins et al (“Impaired oesophageal transit ofcapsule versus tablet formulations in the elderly” Gut. 1994 October 35(10): 1363-1367) (concluding “gelatin capsules showed a clear tendencyto remain within the oesphagus of healthy elderly volunteers, whilesimilar sized enteric tablets did not.”); Channer et al (“The effect ofsize and shape of tablets on their esophageal transit” J Clin Pharmacol.1986 February; 26(2): 141-6) (concluding “large oval tablets hadsignificantly shorter times than did large round tablets” and “retentionof large oval and round tablets in the esophagus occurred in 20% ofpatients after swallowing while in the standing position. No mediumsized tablet was retained, but in 4% of patients, a small tabletremained in the esophagus.”); Perkins et al. (“Esophageal transit and invivo disintegration of branded risedronate sodium tablets and twogeneric formulations of alendronic acid tablets” Clinical Therapeutics,Volume 30, Issue 5, May 2008 pp 834-844) (“the branded risedronatetablet has a significantly faster transit time than the 2 genericformulations of alendronate tested.”); and Perkins et al. (“The use ofscintigraphy to demonstrate the rapid esophageal transit of the ovalfilm-coated placebo risedronate tablet compared to a round uncoatedplacebo tablet when administered with minimal volumes of water” Int JPharm. 2001 Jul. 17; 222(2): 295-303) (observing “no stasis was observedfor the oval film coated placebo risedronate tablet”). Cooker US2004/0101540 A1 posits that oral dosage forms should be more dense: “itis buoyancy that resists the swallowing process.” (Crooker paragraph43). Crooker teaches a solid dosage form that will totally submerge orpartially submerge in water with an intended vertical positioningalignment. Crooker lacks any in vitro (or in vivo) testing methods, andin fact, we show the opposite to be the case.

However, a review of the foregoing literature demonstrates that it isessentially an ad hoc comparison of one existing solid dosage form'sperformance with another. There is no real inquiry into first principlesof tablet design, nor a suggestion to do so, nor any substantiveconclusions concerning the same. Even the question of tablet buoyancy islightly touched upon and incorrectly at that. For representative samplesof the patent art on tableting, see Snowden US 2006/0246136 A1 (Systems,Methods, Apparatuses for Manufacturing Dosage Forms), Berner et al U.S.Pat. No. 6,488,962 (Tablet shapes to enhance gastric retention ofswellable controlled-release), Hampton et al. U.S. Pat. No. 5,213,738(Method for making a capsule-shaped tablet) Lowby U.S. Pat. No.3,166,476 (Powder Based Tablets).

Despite a lack of understanding of tablet design and swallowing,potential damage from esophageal failure is understood in the scientificliterature, if not by the broader medical community. See Jaspersen(cited above), Eckstein et al. (“Iron tablets cause histopathologicallydistinctive lesions in mucosal biopsies of the stomach and esophagus”Pathology 1996 May 28(2): 142-5); Abid et al (Pill-induced esophagealinjury: endoscopic features and clinical outcomes” Endoscopy, 2005August 27(8): 740-4); Maskins et al “Gastrointestinal side effects ofdrugs” Expert Opin Drug Saf. 2003 July 2(4): 421-9), etc.

Each of the foregoing references is specifically incorporated as iffully stated herein, together with all references.

SUMMARY

The present inventors contemplate that substantial benefit to the publichealth could be conferred by the invention of solid dosage forms thatare expressly designed to facilitate rapid and reliable oral, esophagealand GI transit.

We believe that the prior art was not directed at the properunderstanding of the role of the contact patch on the mucosal surfaceand its relation to retarding sticking and the summation of these on theease of transit starting with the oral cavity and tongue and followingon down to the GI tract.

Thus, the present invention relates to a solid dosage form designed tofacilitate rapid and reliable oral, esophageal and GI transit where thesurface area of the contact patch, i.e., the area of contact between thedosage form and the bodily surface, is reduced. The dosage form can bean asymmetric oral dosage unit containing a bioactive, the dosage unitbeing asymmetric with respect to a rotational axis perpendicular to alongitudinal axis of the dosage form, the rotational axis being locatedsubstantially at a mid point along the longitudinal axis. The dosageunit may have an outer surface ridged or dimpled or have at least oneannular ring so as to reduce the contact patch of the dosage unit with aflat surface compared to non-ridged dosage unit (or dosage unit lackingan annular ring) of the same size and shape. The oral dosage unit canalso have a spherical shape.

Dies for forming these oral dosage units have, in a closed state, acavity having a shape corresponding to the oral dosage unit.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of one embodiment of an oral dosage unitof the present invention;

FIG. 1B is a top plan view thereof; and

FIG. 1C is a front elevation view thereof (looking from an angle 90°from that of FIG. 1B).

FIG. 2A is a top plan view of another embodiment of an oral dosage unitof the present invention;

FIG. 2B is a front elevation view thereof (looking from an angle 90°from that of FIG. 2A); and

FIG. 2C is a cross-sectional view along lines 2C-2C of FIG. 2A.

FIG. 3A is a perspective view of still another embodiment of an oraldosage unit of the present invention;

FIG. 3B is a top plan view thereof; and

FIG. 3C is a front elevation view thereof (looking from an angle 90°from that of FIG. 3B).

FIG. 4A is a top plan view of yet another embodiment an oral dosage unitof the present invention;

FIG. 4B is a front elevation view thereof (looking from an angle 90°from that of FIG. 4A); and

FIG. 4C is a right side elevation view (looking from an angle 90° fromthat of FIG. 4A and 90° from that of FIG. 4B).

FIG. 5A is a perspective view of still another embodiment an oral dosageunit of the present invention; and

FIG. 5B is a cross-sectional view along lines 5B-5B of FIG. 5A.

FIG. 6A is a top plan view of yet another embodiment of an oral dosageunit of the present invention; and

FIG. 6B is a side elevation view thereof (looking from an angle 90° fromthat of FIG. 4A and 90° from that of FIG. 6A).

FIG. 7A is a perspective view of still another embodiment an oral dosageunit of the present invention; and

FIG. 7B is a cross-sectional view along lines 7B-7B of FIG. 7A.

FIG. 8A is a partially broken away plan view of yet another embodimentof the present invention showing a spherical oral dosage unit of thepresent invention;

FIG. 8B is a partially broken away plan view of yet another embodimentof the present invention showing a spherical oral dosage unit of thepresent invention containing a variation of the embodiment of FIG. 8A;and

FIG. 8C is a plan view of yet another embodiment of the presentinvention showing a spherical oral dosage unit of the present inventioncontaining a variation of the embodiments of FIGS. 8A and 8B;

FIG. 8D is a plan view of yet another embodiment of the presentinvention showing a spherical oral dosage unit of the present inventioncontaining a variation of the embodiments of FIGS. 8A, 8B and 8C; and

FIG. 8E is a plan view of yet another embodiment of the presentinvention showing a spherical oral dosage unit of the present inventioncontaining a variation of the embodiments of FIGS. 8A, 8B, 8C and 8D.

FIG. 9A is a top plan view of still another embodiment of an oral dosageunit of the present invention;

FIG. 9B is a front elevation view thereof (looking from an angle 90°from that of FIG. 9A); and

FIG. 9C is a cross-sectional view along lines 9C-9C of FIG. 9A.

FIG. 10A is a front elevational view of yet another embodiment of anoral dosage unit of the present invention; and

FIG. 10B is a top plan view thereof (looking at an angle 90° from thatof FIG. 10A).

FIG. 11A is a top plan view of one example of a die for forming oneexample of an oral dosage unit of the present invention; and

FIG. 11B is a cross-sectional view thereof along line 11B-11B of FIG.11A.

FIG. 12A is a top plan view of one example of a die for forming anotherexample of an oral dosage unit of the present invention; and

FIG. 12B is a cross-sectional view thereof along line 12B-12B of FIG.12A.

FIG. 13A is a top plan view of one example of a die for forming yetanother example of an oral dosage unit of the present invention; and

FIG. 13B is a cross-sectional view thereof along line 13B-13B of FIG.13A.

FIG. 14 is graphic representation of the average esophageal transittimes (plotted in the vertical access) of four different tablet shapes.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to comprise and manufacture asolid dosage form designed to promote more rapid and more reliable oral,esophageal and GI transit, as well as to provide some non limitingillustrated die information.

The design of a tablet (or capsule or caplet or liquigel or any soliddosage form) ideally should address the most important factor in adosage unit being difficult to transit—and that is sticking. Sticking isdirectly related of the size of the surface area of the contactpatch—i.e., the area of contact between the dosage form and the bodilysurface. Now in Newtonian physics we are taught that the area of contactdoes not matter in static friction. This does not apply however in thecase of solid dosage form because the moist environment of the GI tractpromotes an adhesion between the mucosa and the typical dosage unitsurface. The propensity to adhere can be greatly reduced by minimizingthe surface area where adhesion can occur. Reducing adhesion promotessuccessful transit. One way that we accomplish this is through theasymmetrical dosage since this results in a substantial reduction in thecontact patch when compared to the symmetrical dosage units we are allaccustomed to. An asymmetric dosage unit will tend to minimize thecontact patch. An additional approach involves a low order symmetricaldesign. An alternative approach is to employ dimples and/or ridgesand/or an annulus or ring on a conventional design or in theaforementioned asymmetric unit in order to reduce the contact surfacearea. Yet another method is to use a sphere or perfectly round ball typedosage unit with or without dimples and/or ridges.

Typically, drugs are evaluated by the FDA for their ability to be safeand effective. Clearly in order to do this they must traverse theesophagus and the GI tract, including but not limited to, the mouth.Since the population of much of the world is aging demographically, manyfactors, such as but not limited to, nutrition, mobility, mental acuity,being bedridden etc. complicate the swallowing and transit of theheretofore known solid dosage units, which had little or noconsideration of the effect of the contact patch size, is no longer aseffective as it may have been perceived. Now, this directly affects theactual absorption dynamics and blood levels of the medication in thegiven patient. Hence in the future, this will be a major factor in adrug's application to therapy. In addition, with the use of anymicrochip and/or camera to the solid dosage form, the importance of thedosage form not being stuck will increasingly be more important.

We demonstrate the value of minimizing the contact patch surface area inour in vitro trial methods that are discussed in the examples hereto.Our in vitro findings are further supported by in vivo trials disclosedherein.

The initial principle expressed by one embodiment of this invention isthat the adhesive contact area of a solid dosage form may be minimizedthrough the use of asymmetric designs—i.e. designs that lack an axis ofsymmetry. The lack of an axis of symmetry means that the dosage unitcannot be rotated and remain the same form except by rotating 360degrees to return to the original position. Even an asymmetric shape mayof course possess a plane of symmetry as that term is understood ingeometry. Low order rotational symmetry, for example, a rotationalsymmetry of order 4 (90°) or order 3 (120°, but preferably an order 2(180°) and most preferably order 1 (360°) are also effective at reducingthe contact area.

When symmetry is discussed in this case, we mean symmetry about arotational axis in the center of the dosage form, such axis beingperpendicular to a longitudinal axis of the dosage form; it is rotated(not tumbled and not rolled) around this axis for purposes of describingsymmetry. Stated another way, if one is looking at the dosage form withits longitudinal axis extending in a horizontal direction, it spinsparallel to the horizontal direction as if rotated from either the leftor right end.

Now, it should be understood that a standard oblong capsule, capletshape (one that is typically employed in common products like ibuprofenand the like) possesses order two symmetry. This design is, as wedemonstrate, sub-optimal for swallowing. As we demonstrate in otherembodiments of the present invention, it is possible to modify symmetricdesigns—by reducing the contact patch—without destroying symmetry. Thiscan be accomplished providing one has either left a core center annularsection in the traditional round mode (which functions as an annulus)and or one rotates one lobe relative to the other lobe. Otherwise thecontact patch will not be reduced. As we demonstrate, one can pinch bothends of a conventional oblong tablet and dramatically improvetransportability through reduction of the contact patch withoutdestroying the order two symmetry of the dosage form providing that thetwo ends are out of phase by one degree or greater and/or a central coreof the capsule/caplet is left un pinched. By “modification” of thedosage form, we mean the use of indentations (convex, concave and othershaped indentations), twists, bends and other changes that reduce thecontact patch area.

We also demonstrate that the use a “bent” dosage form will reduce thecontact patch and enhance transit. We show this in the examples with 90°bend. Lesser and greater angles will tend to work as well. However, asthe angle approaches 0° then the benefit to reducing the contact patchwill also approach zero.

It is demonstrated the reduction of adhesive contact area promotestransit of the dosage form. Furthermore the outward and inward dimplingon asymmetric and symmetric forms is desirable as it lessens contactarea. Similarly, an outgoing ridging is also helpful. Inward dimpling isnot always desirable as this can form a suctional adhesive force on themucosa if Laplace pressures are not kept in mind; however, such suctionshould not be consequential where the dimples are shorter than 3 mm. Insuch instances the Laplace calculation shows that the pressure should bealmost atmospheric.

In another embodiment of the invention, the dosage form can be in theshape of a sphere, preferably, but not necessarily, with dimples, ridgesand/or an annular ring. One disadvantage of the sphere is the propensityto roll on a flat surface which can create difficulties, particularlyfor patients with dexterity issues. In addition a common perceptionmight be that this shape is easier to choke on. The evidence is thatthis is not so, however, this is a common perception. In addition if oneadds dimples and/or ridges and/or an annulus to this form the contactpatch will be reduced. Lastly, the aforementioned modifications increasethe ability of a water bolus to dislodge and move the dosage unit due tothe paddle wheel effect (and the reduced contact patch) which natureuses in something like but not limited to the maple “helicoptor” seedwhich in nature must be moved readily by water and wind to reach fertilesoil. This can be seen if one, in quiet observation, watches theseproducts of nature work themselves off of a solid object like a rocketc.

It may also be desirable to use a surface coating with a relativelubricity factor and a low adhesive characteristic. It may alsodesirable to use a hydrophobic coating to retard disintegration andsubsequent adhesion in the esophagus. A wax like coating, as anon-limitative example could function well as an additional factor. Alubricity agent may be applied by spray coating, film coating and othermethods understood could also be an additional factor. It may bedesirable to specifically locate the lubricity agent in the annularring, dimples, ridges or other protrusion. It may also be desirable touse dosage form excipients that are not quick to disintegrate or tack,particularly where the dosage form is not coated as this could beadditive to the invention. The key here is to reduce disintegration orsurface characteristics that would result in adherence. However, tosummarize this topic, first the drug itself must be delivered andtherefore the dosage unit must disintegrate and not be so hydrophobic asto adversely interfere with the intended disintegration (typically inthe GI tract). In addition, it is important that the material used onthe dosage unit surface, as a material from a material science point ofview, be as adhesion resistant as possible. After that is accomplishedthe design as discussed in this application is pivotal.

It may be desirable to use an annular ring wherein the materialcomprising the annular ring as different disintegration properties thanthe rest of the composition, i.e. either faster or slower.

Interestingly, while Hey states (and Cooker conjectures) that increaseddensity will enhance tablet transit, we found that reduced densityimproves transit performance of a solid dosage form through an improvedrelative buoyancy. This makes logical sense, as the water swallowed hasa more beneficial effect if the buoyancy of the dosage form is greater.Density can be controlled through the use of more or less denseexcipients (e.g. silicates to lighten as a non-limitative example). Theliterature demonstrates that a substantial number of esophageal transitissues arise in the case of supine and semi-supine administration. Weteach—and demonstrate—that adhesionary forces tend to create transitfailure. The low contact patch with additional buoyancy, will—in thepresence of water—be kept from substantial contact with the esophageallining where adhesion can occur (implying a specific gravity of lessthan one, preferably less than 0.65). This leads to rapid, reliable,successful esophageal transit. It is known that a high number of newdrugs NCE's are low dosage potent forms. Thus the possibility exists togive broad access to density modification.

The current invention can be readily made using existing capsulesystems, by merely altering the shape of one of the capsule shells. Thetableting process can be modified to accommodate the current invention.This would involve a tableting dies that are asymmetric themselves inorder to turn out the tablet, capsule, caplet. liquigel etc. Similarly,a ridged die tooling that is female product is counter ridged toresulted in pushed out ridges (or the converse). Dies may also be inwardand outward dimpled in order to turn out male/female dimpled forms.

Still another method of manufacturing the current invention is to make asoftgel product and then mold the product after conventional manufactureto the desired shape. It may be desirable to adjust the elasticity ofthe softgel material, as well as reduce the fill level of the softgel aswell as modify other parameters in order to minimize the danger ofpuncture to the softgel during this secondary re-shaping process.Various plasticizers and related agents may be useful for thesepurposes. In addition there is no need to reduce the fill level if thisis a product which is made this way and yet the fill level may bemodified.

All of these designs involve some very unique mold forms for the pressesand tablet and liquigel and capsule machines that make them. It isintended that the scope of this invention include these molds as well.

Similarly, one may use a secondary re-shaping process with conventionalcapsules assuming sufficient elasticity (and low fill volume) for thecapsule. It is further contemplated that the shape of a conventional,symmetrical dosage may be altered through the use of a sort ofprosthesis for tablets, made of GRAS or other acceptable materials. Sucha method allows for the use of existing tablet dies and capsulemanufacture followed by the secondary addition of the form prosthesis.

Any embodiment of the dosage unit of the present invention may containan RFID tag antenna or its equivalent. An asymmetric dosage unit alsocontains an ideal location for an RFID tag antenna or its equivalent andcan minimize the tablet substance that the radio wave must traverse.Furthermore, the use of a computer type chip can be idealized by usingthese asymmetric principles shown here. Also, the emerging use ofminiature recording cameras for inside the GI tract can benefit fromthese asymmetric shapes by allowing for better placement of electronics.

An additional aspect of the current invention is that the improvedesophageal transit performance of the various designs taught hereinallow one to increase the relative load that can be reliably transited.Stated more simply, people have trouble swallowing large tablets and theeasing of the swallowing of larger tablets has clear benefits. This alsoallows for the using of various methods that are otherwise impracticablein a single dosage form, such as low loading sustain release methodslike ion exchange or certain coating methods or other binder systems.This further allows for the use of increased amounts of agents toenhance or retard absorption such as buffering agents (including withoutlimitation staged buffering agents), penetration enhancers and otherexcipients to enhance (and retard) release, delivery and absorption.Also, microchips, smart capsules with a drug reservoir for site specificdelivery and/or cameras and other recording devices are more easilyswallowed (and size of payload—and thus room for these items can beincreased). See Fuisz U.S. Pat. No. 7,899,705 and www.proteusbiomed.com.

The bioactive agent of the present invention is preferably apharmaceutical but may be any biological, antigen, botanical, food ornutraceutical, cosmaceutical, gene therapeutic or other active agent. Itmay also comprise a tablet camera or other diagnostic device or drugdelivery device that is contemplated to be swallowed.

Examples of pharmaceutical bioactive agents include, but are not limitedto ace inhibitors, such as Benazepril, Captopril, Enalapril, Lisinopril,Moexipril, Perindopril, Quinapril, Ramipril and Trandolapril; acnetreatments, such as adapalene, azelaic acid, BenzaClin, Benzamycin,Benzoyl Peroxide, clindamycin, Duac, Erythromycin, Glycolic Acid,Isotretinoin, Sulfacetamide with sulfur, Tazarotene and Tretinoin;actinic keratosis, such as declofenac, fluorouracil; addiction aids,such as buprenorphine, Disulfuram, Naltrexone, Suboxone and varenicline;aldosterone antagonists, such as eplerenone and spironolactone; alpha-1adrenergic blockers, such as alfuzosin, doxazosin, prazosin, tamsulosinand terazosin; ALS agents, such as riluzole; Alzheimer's Diseasemedications, such as donepezil, Galantamine, rivastigmine, tacrine andmemantine; anesthetics, such as dexmedetomidine, etomidate, ketamine,methohexital, pentobarbital, propofol and thiopental; angiotensin IIreceptor blockers, such as candesartan, eprosartan mesylate, irbesartan,losartan, olmesartan, telmisartin and valsartan; antacids, such asAluminum hydroxide, AlOH and magnesium trisilicate; anti-arrhythmics,such as adenosine, amiodarone, Atropine, Bretylium, digoxin-Immune Fab,disopyramide, dofetilide, epinephrine, Esmolol, flecainide, ibutilide,isoproterenol, lidocaine, mexiletine, moricizine, procainamide,propafenone, quinidine, sotalol, tocainide and verapamil; antibiotics,such as Aztreonam, TMP/SMX, Chloramphenicol, Clindamycin, Dapsone,Daptomycin, Ertapenem, Imipenem/cilastatin, Linezolid, Meropenem,Metronidazole, Nitrofurantoin, Quinupristin/Dalfopristin, Rifaximin,Tigecycline, Telithromycin and Tinidazole; anticholinergic acids, suchas Dicyclomine, Donnatal, Flavoxate, Glycopyrrolate, Hyoscyamine,Oxybutynin, Propantheline and Tolterodine; anticonvulsants, such ascarbamazepine, clonazepam, diazepam, ethosuximide, felbamate,fosphenytoin, gabapentin, levetiracetam, lamotrigine, lorazepam,Oxcarbazepine, Phenobarbital, phenyloin, pregabalin, primidone,tiagabine, topiramate and valproic acid; antidepressants, such asamitriptyline, buproprion, citalopram, desipramine, doxepin, duloxetine,escitalopram, fluoxetine, fluvoxamine, imipramine, mirtazapine,nefazodone, nortriptyline, nortriptyline, sertraline, trazodone andvenlafaxine; anti-diarrheals, such as dephenoxylate+atropine, Imodiumand bismuth subsalicylate; anti-emetics, such as Aprepitant, dolasetron,droperidol, granisetron, metoclopramide, ondansetron, prochlorperazine,scopolamine and trimethobenzamide; antifungals, such as Ampho B, Ampho Blipid, anidulafungin, caspofungin, Clotrimazole fluconazole,flucytosine, Griseofulvin, Itraconazole, ketoconazole, Micafungin,nystatin, Posaconazole, terbinafine, voriconazole, butenafine,ciclopirox, clotrimazole, enconazole, ketoconazole, Miconazole,naftifine, nystatin, oxiconazole terbinafine and Tolnaftate;anti-hepatitis, such as adefovir, entecavir, lamivudine, peginterferonaifa-2a, peginterferon aifa-2b, Rebetron and ribavirin; anti-herpeticagents, such as Acyclovir, famciclovir, valacyclovir, acyclovir,docosanol and penciclovir; antihistamines, such as cetirizine,desloratadine, fexofenadine, loratadine, chiorpheniramine, ciemastine,cyproheptadine, dimenhydrinate, diphenhydramine, hydroxzine andpromethazine; anti-hypertension, such as Benazepril & HCTZ, Captopril &HCTZ, Enalapril & HCTZ, Lisinopril & HCTZ, Moexipril & HCTZ, Losartan &HCTZ, Vaisartan & HCTZ, Atenolol & chiorthalidone, Bisoprolol & HCTZ,Metoprolol & HCTZ, Nadolo! & bendrofiumethazide, Propranolol & HCTZ,Timolol & HCTZ, Amlodipine & benazepril, Verapamil & trandolapril,Amiloride & HCTZ, Spironolactone & HCTZ, Triamterene & HCTZ, Clonidine &chiorthalidone, Hydralazine & HCTZ, Methyldopa & HCTZ and Prazosin &polythiazide; anti-hypertensives, such as Aliskiren, Aliskiren,epoprostenol, fenoldopam, hydralazine, minoxidil, nitroprusside,phentolamine and treprostinil; anti-influenza agents, such asamantadine, oseltamivir phosphate, rimantadine and zanamivir;anti-malarials/anti-protozoals/amebicides, such as Atovaquone,Chloroquine, Iodoquinol, Mefloquine, Primaquine, Pyrimethamine,Pyrimethamine-Suifadoxine and Quinine Sulfate; anti-platelet agents,such as abciximab, dipyridamole/ASA, anagrelide, cilostazol,clopidogrel, dipyridamole, eptifabatide, ticlopidine and tirofiban;antipsychotics, such as aripiprazole, chlorpromazine, Clozapine,fluphenazine, haloperidol, loxapine, molindone, olanzepine,perphenazine, pimozide, quetiapine, risperidone, thioridazine,thiothixine, trifluoperazine, ziprasidone and Lithium; antispasmotics,such as Dicyclomine, Donnatal Extentabs, Propantheline, Simethicone,hyoscyamine, Librax, tegaserod and Bellergal-S;anti-tussives/expectorants, such as Benzonatate and guaifenesin; atopicdermatitis medications, such as pimecrolimus and tacrolimus;benzodiazepines and non-benzodiazepine sedatives, such as aiprazolam,buspirone, chlordiazepoxide, chlorazepate, cionazepam, diazepam,estazolam, eszcpiclone, flurazepam, lorazepam, midazolam, Oxazepam,ramelteon, temazepam, triazolam, zaleplon and zolpidem; beta blockers,such as atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol,metoprolol, nadolol, pindolol, propranolol, sotalol and timolol; bileacid sequestrants, such as cholestyramine, colesevelam and colestipol;bisphosphonates, such as alendronate, etidronate, pamidronate,risedronate, tiludronate and Zoledronic acid, Raloxifene andTeriparatide; bladder spasm medications, such as flavoxate, hyoscyamine,darifenacin, oxybutynin, soiifenacin, tolterodine and trospium; benignprostatic hypertrophy medications, such as alfuzosin, doxazosin,dutasteride, finasteride, tamsulosin and terazosin; burn preparations,such as mafenide acetate and silver sulfadiazine; calcium channelblockers, such as amlodipine, bepridil, diltiazem, felodipine,isradipine, nicardipine, nifedipine and nisoldipine; calciumsupplements, such as Calcium and Hypocalcemia; cephalosporins, such asCefadroxil, Cefazolin, Cephradine, Cephalexin, Cefaclor, Cefotetan,Cefoxitin, Cefprozil, Cefuroxime, Cefuroxime, loracarbef, Cefdinir,Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime,Ceftibuten, Ceftizoxime and Cefepime; colony stimulating factors, suchas darbepoietin alfa, erythropoietin, filgrastim, oprelvekin,pegfilgrastim and sargramostim; corticosteroids, such as Budesonide,cortisone acetate, dexamethasone, fludrocortisones, hydrocortisone,methylprednisolone and prednisone; corticosteroids Intra-articular, suchas Depo-Medrol and Triamcinolone Acetonide; cystitis, such as pentosanpolysulfate, Bethanecol and Alum irrigation; decongestants, such asPhenylephrine and Pseudoephedrine; anti-diabetic agents, such asacarbose, Miglitol and metformin, Avandamet®, Glucovance, Metaglip,Metaglip, rosiglitazone, osiglitazone, repaglinide, Chlorpropamide,glimepiride, glyburide, glipizide, Tolazamide, Tolbutamide, Glucagon,extenatide and pramlintide; direct thrombin inhibitors, such asargatroban, Bivalirudin and lepirudin; disease modifying agents, such asadalimumab, anakinra, auranofin, azathioprine, etanercept,hydroxychloroquine, infliximab, leflunomide, methotrexate andsulfasalazine; diuretics, such as Acetazolamide, Amiloride, Amilorideand HCTZ Bendroflumethiazide, Bumetanide, Chlorothiazide,Chlorthalidone, Dichlorphenamide, Eplenerone, Ethacrynic acid,Furosemide, Hydrochlorothiazide, HCTZ rrriampterene, Hydroflumethiazide,Indapamide, Methazolamide, Methyclothiazide, Methyclothiazide,Metolazone, Polythiazide, Spironolactone, Spironolactone, HCTZTorsemide, Trichlormethiazide and Triamterene; endocrine agents, such asbromoc cinacalcet cosyntropin, riptine, cabergoline, calcitonin,desmopressin, Leuprolide, octreotide and vasopressin; erectiledysfunction agents, such as Sildenafil, tadalafil, vardenafil; fevermedications, such as allopurinol, antihistamines, azathioprine,barbiturates, carbamazepine, cephalosporins, cimetidine, folic acid,hydralazine, hydroxyurea, ibuprofen, isoniazid, methyldopa,nitrofurantoin, penicillins, phenyloin, phenyloin, procainamide,prophylthiouracil, quinidine, streptomycin sulfonamides, sulindac,triamterene and vancomycin; fibrates, such as ciofibrate, fenofibrat andgemfibrozil; fluoroquinolones, such as Ciprofloxacin, Gatifloxacin,Levofloxacin, Moxifloxacin, Norfloxacin and Ofloxacin; gastrointestinalagents, such as Alosetron, infliximab, Mesalamine, misoprostol,Neomycin, octreotidev, osaiazine, Orlistat, sucralafate, Sulfasalazineand vasopressin; gout treatments, such as allopurinol, coichicine,probenecid, Rasburicase and sulfinpyrazone; H2 receptor blockers, suchas cimetidine, famotidine, nizatidine and ranitidine; Anti-herpeticagents, such as Acyclovir, famciclovir, valacyclovir, acyclovir,docosanol and penciclovir; hypertensive urgency, such as Captopril,Clonidine and Labetalol; hypertensive emergency, such as Enalaprilat,Esmolol, Fenoldopam mesylate, Hydralazine, Labetalol, Nicardipine,Nitroglycerin and Sodium nitroprusside; hemorrhoidal preparations, suchas Anusol HC, Anusol Suppository, Dibucaine, pramoxine 1%, Proctofoam-HCand Analpram-HC; inflammatory bowel disease agents, such as balsalazide,budesonide, infliximab, mesalamine, olsalazine and sulfasalazine;Interferon, such as Interferon Alfa-2A, Interferon Alfa-2b, InterferonAlfa-2b and Ribavirin combo Pack, Interferon Alfa-N3, InterferonBeta-1A, Interferon Beta-1B (Betaseron); intermittent claudication, suchas ciiostazol and pentoxifylline; immunizations, such as Comvax,diphtheria-tetanus toxoid, Hepatitis A vaccine, Hepatitis B vaccine,Influenza vaccine, Fluzone, Lyme disease vaccine, PNEUMOVAX* 23;laxatives, such as Bisacodyl, Cascara, Docusate, Fleet Phospho-Soda,Glycerin, Lacalutose, lubiprostone, Magnesium citrate, Magnesiumhydroxide—MOM, Mineral Oil, Pericolace, Psyllium and Senna; lowmolecular weight heparins, such as dalteparin, danaparoid, enoxaparin,tinzaparin, fondaparinux; macrolides, such as Azithromycin,Clarithromycin and Erythromycin; magnesium, such as magnesium salt;migraine treatments, such as almotriptan, eletriptan, frovatriptan,naratriptan, rizatriptan, sumatriptan, zolmitriptan, Cafergot®,Cafergot®, dihydroergotamine and Midrin®; mouth and lip treatments, suchas amlexanox, Benzocaine, carbamide, peroxide, Kenalog in Orabase®,Phenol, chlorhexidine gluconate, clotrimazole, Nystatin, Penciclovir,docosanol, Gelclair, lidocaine viscous, BMX Cocktail, Pilocarpine andArtificial saliva; multiple sclerosis treatments, such as glatiramer,interferon beta-1A and interferon beta-1 B; muscle relaxants, such asbaclofen, carisprodol, cyclobenzaprine, cyclobenzaprine, Diazepam,Metaxalone, Methocarbamol, Orphenadrine; nasal preparations, such asazelastine, beclomethasone, budesonide, cromolyn, desmopressin acetate,fiunisolide, fluticasone, Ipratropium bromide, mometasone,oxymetazoline, phenylephrine, Saline nasal spray, Sumatriptan,triamcinolone and Zolmitriptan; urology treatments, such as Belladonnaand opium, flavoxate, hyoscyamine, hyoscyamine, oxybutynin, solifenacin,tolterodine and trospium; neuromuscular blockers, such as Atracurium,Cisatracurium, doxacurium, mivacurium, pancuronium, Rocuronium,Succinylcholine, vecuronium, Mivacurium, Rapacuronium, Rocuronium,Succinylcholine, Atracurium, Cisatracurium, Pancuronium, Vecuronium,Doxacurium, Pipecuronium and Tubocurarine; nitrates, such as Isosorbidedinitrate, Isosorbide mononitrate, Nitroglycerin ointment, Nitrobid andNitroglycerin transdermal; NSAID's, such as Arthrotec, diclofenac,Etodolac, indomethacin, Ketorolac, Sulindac, Tolmentin DiflunisalSalsalate Meloxicam, piroxicam, Nabumetone Flurbiprofen, Ibupropen,Ketoprofen, Naproxen, Oxaprozin, celecoxib, Rofecoxib and Valdecoxib;ophthalmic agents, such as, proparacaine, tetracaine, Ciprofloxacin,Erythromycin, Gentamcyin, levofloxacin, levofloxacin, norfloxacin,Ofloxacin, Polysporin®, Polytrim, Sulfacetamide, Tobramycin,Blephamide®, Blephamide®, Maxitrol®, Pred G®and TobraDex®,Dexamethasone, Fluorometholone, Loteprednol, Prednisone, Rimexolone,azelastine, Cromolyn sodium, emedastine, Epinastine, Ketotifen FumarateOphthalmic Solution 0.025.degree./o, Levocabastine, Lodoxamidetromethamine, Naphazoline, Naphcon-A®, nedocromil, Olopatadine,pemirolast, Betaxolol, Betaxolol, Levobunolol, TimoloE, Brinzolamide,Dorzolamide, Pilocarpine, bimatoprost, Latanoprost, travoprost,unoprostone, Apraclonidine, Brimonidine, Cosopt® and Cosopt®, Atropine,Cyclopentolate, Homatropine, Phenylephrine, Phenylephrine, Diclofenac,Flurbiprofen and Ketorolac; ear (otic) preparations, such as Auralgan®,carbamide peroxide, CIPRODEX®, Ciprofloxacin and hydrocortisone,Cortisporin®, Ofloxacin, Triethanolamine and Vosol Otic®; opiates, suchas Codeine Fentanyl Hydrocodone Hydrocodone, Meperidine Methadone,morhphine, xycodone, Propoxyphene, Darvon®, Fioricet, Fiorinal, Somacompound, Tramadol, Anexsia, Darvocet, Darvon Compound, Lorcet, Lortab,Percocet, Percodan, Roxicet, Tylenol with Codeine, Tylox, Vicodin,Wygesic, Buprenorphene, Butorphanol, Dezocine, Nalbuphine, Pentazocine,Nalmefene Naloxone, Suboxone® and Ziconotide; parkinson's diseasetreatments, such as amantadine, benztropine, bromocriptine, entacapone,pergolide, pramipexole, ropinirole, selegiline, Sinemet®, tolcapone andtrihexyphenidyl; PCA—Patient Controlled Analgesia, such as Fentanyl,Hydromorphone, Meperidine and Morphine; penicillin's, such asAmpicillin, Ampicillin/sulbactam, Amoxicillin, Amoxicillin/Clavulanate,Cloxacillin, Dicloxacillin, Nafcillin, Penicillin G, Penicillin VK,Piperacillin, Piperacillin/Tazobactamm, Ticarcillin, andTicarcillin/Clavulanate; phosphate supplementation, such as, K-Phos®Neutral Tablets, K-PHOS® ORIGINAL, Neutra-Phos®; potassiumsupplementation, such as K-LOR, Klor-Con®, Potassium depletion; prostatecancer medications, such as bicalutamide, flutamide, gosereiin,leuprolide and nilutamide; proton pump inhibitor's, such asesomeprazole, Lansoprazole, Omeprazole, Pantoprazole and RabeprazoleSodium; psoriasis medications, such as acitretin, aiefacept, Anthralin,Caicipotriene, efalizumab and Tazarotene; renal failure medications,such as Aluminum Hydroxide, Calcium acetate, Calcitriol,Doxercalciferol, Ferric Sodium Gluconate, paricalcitol and sevelamer;pulmonary medications, such as ipratropium, tiotropium, albuterol,bitolterol, levalbuterol, pirbuterol, metaproterenol, formoterol,salmeterol, Advair®, Symbicort®, beclomethasone, budesonide,flunisofide, fluticasone, Mometasone furoate, triamcinolone, montelukastSingulair®, zafirlukast, cromolyn sodium, nedocromil, acetylcysteine andaminophylline/theophyliine; disease modifying agents, such asadalimumab, anakinra, auranofin, azathioprine, etanercept,hydroxychloroquine, infliximab, leflunomide, methotrexate andsulfasalazine; HMG COA reductase inhibitors, such as Atorvastatin,Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin,Advicor®, Vytorin® and ezetimibe; stimulants, such as atomoxetine,benzphetamine, Caffeine, dexmethylphenidate, Dextroamphetamine,diethylpropion, Methylphenidate, Modafinil, Pemoline, phendimetrizine,phentermine and sibutramine; tetracyclines such as Doxycycline,Minocycline and Tetracycline; thrombolytic agents such as Alteplase;anti-thyroid agents such as methimazole and propylthiouracil; toxicologyrelated medications such as acetylcysteine, Charcoal, deferoxamine,digoxin immune fab, flumazenil, fomepizole, methylene blue, naloxone,sodium polystyrene sulfonate and Sorbitol; anti-mycobacterial agentssuch as Ethambutol, Isoniazid, Pyrazinamide, rifabutin, Rifamate,Rifampin, Rifapentine and Rifater; topical products such asAlitretinoin, Becaplermin, Calamine, Capsaicin, Doxepin,lidocaine/prilocalne, fluorouracil, Masoprocol, Pimecrolimus, Seleniumsulfide and Tacrolimus; topical anti-viral agents such as acyclovir,docosanol, imiquimod, penciclovir, podofilox and podophyllin; topicalantibacterials such as bacitracin, rnetronidazole, mupirocin,bacitracin/neomycin/polymyxin, bacitracin/polymyxin and silversulfadiazine; topical antifungals such as butenafine, ciclopirox,clotrimazole, econazole, ketoconazole, miconazole, naftifine, nystatin,oxiconazole, terbinafine and tolnaftate; topical anti-parasitic agentssuch as Crotamiton, Lindane, Permethrin, pyrethrins and piperonylbutoxide; topical burn preparations such as mafenide acetate and silversuifadiazine; topical corticosteroids such as Aclometasonediproprionate, Desonide, Flucinolone acetonide, Hydrocortisone,Betamethasone dipropionate, betamethasone valerate, clocortolonepivalate, desoximetasone, fluocinolone acetonide, flurandrenolide,fluticasone propionate, Chydrocortisone butyrate, hydrocortisonevalerate, mometasone furoate, prednicarbate, triamcinoione, amcinonide,augmented betamethasone dipropionate, betamethasone dipropionate,desoximetasone, diflorasone diacetate, fluocinalone acetonide,fluocinonide, halcinonide, clobetasol propionate, difiorasone diacetateand haiobetasol propionate; urology medications such as pentosanpolysulfate, Bethanecol and phenazopyridine; vaginal preparations suchas clindamycin, metronidazole, butoconazoie, clotrimazole, miconazoie,terconazole and tioconazole; vasodilators such as Fenoldopam mesylate,Hydralazine, Nesiritide, Nicardipine, Nitroglycerin, and SodiumNitroprusside; and vasopressors and inotropes such as Dobutamine,Dopamine, Epinephrine, inamrinone, Milrinone, Norepinephrine,Phenylephrine, and Vasopressin.

Examples of food or nutraceutical bioactive agents include, but are notlimited to, constituents in foods or dietary supplements that areresponsible for changes in health status, such as components of plants,especially fruits and vegetables, e.g., soy which contains isoflavonesand phytoestrogens, tomatoes which contain lycopene that may haveanticancer properties, berries such as blueberries and raspberries whichcontain flavonoids like anthocyanins that may act as antioxidants, greentea which contains epigallocatechin gallate (EGCG) that may haveanticancer properties, resveratrol from red grape products as anantioxidant, soluble dietary fiber products, such as psyllium seed huskfor reducing hypercholesterolemia, broccoli (sulforaphane) as a cancerpreventative, and soy or clover (isoflavonoids) to improve arterialhealth. Flavonoids, antioxidants, alpha-linolenic acid from flax seeds,extracts such as ginseng, garlic oil, etc. Examples of biologicalbioactive agents include, but are not limited to biologically activesubstances in plants that have proven (e.g. cholesterol lowering effectsof phytosterols) or potential beneficial effects on health, i.e.,phytochemicals or phytonutrients, in particular phytochemicals inleaves, stems, roots, tubers, buds, fruits, seeds and flowers, and plantderived foods and drinks (such as tea, coffee, alcoholic beverages),such as flavonoids found in a range of plant derived foods includingtea, wine, onions, apples and berries, glucosinolates from Cruciferousvegetables, phenolic acids in tea and coffee for example, andcarotenoids (some of which are precursors of vitamin A) prevalent inred, green and orange fruits and vegetables.

Examples of antigen bioactive agents include, but are not limited toexogenous antigens, endogenous antigens, autoantigens and tumorantigens. Exogenous antigens are antigens that have entered the bodyfrom the outside, for example by inhalation, ingestion, or injection. Byendocytosis or phagocytosis, these antigens are taken into theantigen-presenting cells (APCs) and processed into fragments. APCs thenpresent the fragments to T helper cells (CD4.sup.+) by the use of classII histocompatibility molecules on their surface. Some T cells arespecific for the peptide:MHC complex. They become activated and start tosecrete cytokines. Cytokines are substances that can activate cytotoxicT lymphocytes (CTL), antibody-secreting B cells, macrophages, and otherparticles. Endogenous antigens are antigens that have been generatedwithin the cell, as a result of normal cell metabolism, or because ofviral or intracellular bacterial infection. The fragments are thenpresented on the cell surface in the complex with MHC class I molecules.If activated cytotoxic CD8+ T cells recognize them, the T cells begin tosecrete various toxins that cause the lysis or apoptosis of the infectedcell. In order to keep the cytotoxic cells from killing cells just forpresenting self-proteins, self-reactive T cells are deleted from therepertoire as a result of tolerance (also known as negative selection).They include xenogenic (heterologous), autologous and idiotypic orallogenic (homologous) antigens. An autoantigen is usually a normalprotein or complex of proteins (and sometimes DNA or RNA) that isrecognized by the immune system of patients suffering from a specificautoimmune disease. These antigens should, under normal conditions, notbe the target of the immune system, but, due to mainly genetic andenvironmental factors, the normal immunological tolerance for such anantigen has been lost in these patients. Tumor antigens or Neoantigensare those antigens that are presented by MHC I or MHC II molecules onthe surface of tumor cells. These antigens can sometimes be presented bytumor cells and never by the normal ones. In this case, they are calledtumor-specific antigens (TSAs) and, in general, result from atumor-specific mutation. More common are antigens that are presented bytumor cells and normal cells, and they are called tumor-associatedantigens (TAAs). Cytotoxic T lymphocytes that recognize these antigensmay be able to destroy the tumor cells before they proliferate ormetastasize. Tumor antigens can also be on the surface of the tumor inthe form of, for example, a mutated receptor, in which case they will berecognized by B cells.

Examples of botanical bioactive agents include, but are not limited toPM1-004 (advanced botanical formulation for type II diabetes—Representsa multi-mechanism bioactive that: 1) in adipocytes increases adiponectinsecretion, 2) in the liver lowers PEPCK expression, and 3) in musclecells increases cellular signaling through the insulin receptor pathway,increasing glucose uptake, glycogen synthase, and glycogenaccumulation.), PMI-005 (botanical bioactive, derived from a commonvegetable, that inhibits gene expression of a variety ofpro-inflammatory cytokines (including a-TNF, i-NOS, 1 L-1b, and COX-2).Currently undergoing a human clinical trial in osteoarthritis. Also mayhave utility in the management of severe/life threatening inflammatoryconditions, such as in the management of the septic patient.), PM1-006(botanical bioactive, derived from a spice, that inhibits a range ofinflammation-related enzymes (including a-TNF and COX-2). Also possessesrange of novel bioactivities related to both lipid and glucosemetabolism (RXR receptors).), PMI-007 (a powerful, centrally acting,botanical appetite suppressor which acts via a unique central pathway inthe nutrient-sensing hypothalamic neurons by increasing ATPcontent/production. It possesses potent anorectic activity withouttypical CNS appetite suppressor side effects. Pre-clinical data hasshown that the agent suppresses both appetite and reduces weight inanimal models, while there is supporting clinical evidence of humanefficacy.), PM1-008 (botanical bioactive, derived from an agriculturalwaste processing stream, that blocks fat accumulation/absorption andpromotes weight loss via interaction with a variety of lipases includingPL, LPL, and HSL.), and PMI-016 (a powerful, plant-derivedanabolic/ergogenic agent, with no androgenic side effects; could be usedin a range of human muscle wasting disorders, including those associatedwith both cancer and AIDS, as well as general aging (sarcopenia). Thisagent has been shown to induce protein synthesis in muscle cells(similar to IGF) and promote a reduction in protein degradation, whileit has also been shown to increase growth hormone gene transcription anddecrease in ubiquitin protein ligase gene transcription. PM1-016 showsno binding to testosterone receptor in contrast to anabolic steroids.).

The FDA defines drugs as products that “cure, treat, mitigate or preventdisease or that affect the structure or function of the human body.”Cosmetic products are defined by the FDA as “articles intended to berubbed, poured, sprinkled, or sprayed on, introduced into, or otherwiseapplied to the human body . . . for cleansing, beautifying, promotingattractiveness, or altering the appearance.” Although cosmaceuticalproducts have properties of both groups, the FDA lumps them under thedefinition of cosmetics, and they are not recognized as a distinctcategory. Because cosmaceutical products are not included in the FDA'sdefinition of drugs, they are not subject to the same regulations,restrictions, and testing.

It should be noted that on those dosage units that are medicallyappropriate to break into, e.g., two (or more) equal dosage forms, atraditional score mark can be present. Based on the above, that scoremark may or may not be in the traditional location, i.e., in the middleof the dosage unit, but can be at a location that divides the dosageunit into two (or more) equal volumes. While spherical or ball-likedosage units (with and/or without dimples and ridges) can theoreticallybe scored, the spherical shape makes it difficult to cleave. Adding anannular ring makes it even more difficult to cleave a sphere. Thus, aspherical dosage unit (with and/or without dimples, ridges and/or anannular ring) is most appropriate for dosage units that are medicallynot intended to be broken or cleaved.

FIG. 1A is a perspective view of one embodiment of an oral dosage unitof the present invention; FIG. 1B is a top plan view thereof; and FIG.1C is a front elevation view thereof (looking from an angle 90° fromthat of FIG. 1B). FIGS. 1A-1C show a “modified” gel cap or tablet 10that has been modified by to render the gel cap pinched (thinner) at oneend 12 (the left end shown in these figures). The other end 14 (theright end in the figures) can, in this embodiment, retain its standard,e.g., generally cylindrical form, as can be seen from FIGS. 1B and 1C.In the embodiment shown in FIGS. 1A-1C, as an example only, the pinched(thinner) 12 is wider than the other end 14 (see, FIG. 1B). The modifiedgel cap or tablet 10 is asymmetric. Thus, FIGS. 1A-1C show an asymmetricoral dosage unit 10 that is asymmetric with respect to a rotational axisRA in the center (center meaning the mid portion along the longitudinalaxis) of the dosage unit, the rotational axis RA being perpendicular toa longitudinal axis of the dosage form. If desired, both ends of thedosage unit 10 can be made pinched or thinner if the pinched or thinnedends are more than 0° and less than 180° out of phase with respect tothe longitudinal axis.

In the asymmetric oral dosage unit of FIGS. 1A-1C, the dosage unit 10has opposing end portions 12 and 14 along the longitudinal axis, one endportion 14 having a substantially cylindrical shape and an opposite endportion 12 having a flattened area with a thickness smaller than an aradius of the cylindrical portion 14.

FIG. 2A is a top plan view of another embodiment of an oral dosage unitof the present invention; FIG. 2B is a front elevation view thereof(looking from an angle 90° from that of FIG. 2A); and FIG. 2C is across-sectional view along lines 2C-2C of FIG. 2A.

FIGS. 2A-2C show a “modified” gel cap, capsule or tablet 20 that hasbeen modified by to render the gel cap, capsule or tablet pinched(thinner) at one end 22 (the left end shown in these figures) and tohave a concave depression 23. The other end 24 (the right end in thefigures) can, in this embodiment, retain its standard, e.g., generallycylindrical form, as can be seen from FIGS. 2B and 2C. In the embodimentshown in FIGS. 2A-2C, as an example only, the pinched (thinner) 22 iswider than the other end 24 (see, FIG. 2A). The modified gel cap ortablet 20 is asymmetric. Thus, FIGS. 2A-2C show an asymmetric oraldosage unit 20 that is asymmetric with respect to a rotational axis RAin the center of the dosage unit, the rotational axis RA beingperpendicular to a longitudinal axis of the dosage form. If desired,both ends of the dosage unit 20 can be made pinched or thinner and oneor both ends can have concave depressions, if the pinched or thinnedends are more than 0° and less than 180° out of phase with respect tothe longitudinal axis.

While FIGS. 2A-2C show a gel cap, capsule or tablet 20 having a concavedepression 23, it can alternatively have a convex protrusion instead ofthe concave depression 23.

FIG. 3A is a perspective view of still another embodiment of an oraldosage unit of the present invention; FIG. 3B is a top plan viewthereof; and FIG. 3C is a front elevation view thereof (looking from anangle 90° from that of FIG. 3B).

FIGS. 3A-3C show a “modified” gel cap, capsule or tablet 30 that hasbeen modified by to render the gel cap, capsule or tablet pinched(thinner) at both ends 32 and 34 and to have concave depressions 33 and35. The pinched or thinned ends are more than 0° and less than 180° outof phase with respect to the longitudinal axis, i.e., 90° out of phasewith respect to the longitudinal axis in this embodiment. In thisembodiment, none of the gel cap or tablet has a standard, e.g.,generally cylindrical form. The modified gel cap or tablet 30 isasymmetric. Thus, FIGS. 3A-3C show an asymmetric oral dosage unit 30that is asymmetric with respect to a rotational axis RA in the center ofthe dosage unit, the rotational axis RA being perpendicular to alongitudinal axis of the dosage form.

While FIGS. 3A-3C show a gel cap, capsule or tablet 30 having concavedepressions 33 and 35, it can alternatively have convex protrusionsinstead of the concave depressions 33.

FIG. 4A is a top plan view of yet another embodiment an oral dosage unitof the present invention; FIG. 4B is a front elevation view thereof(looking from an angle 90° from that of FIG. 4A); and FIG. 4C is a rightside elevation view (looking from an angle 90° from that of FIG. 4A and90° from that of FIG. 4B).

FIGS. 4A-4C show a “modified” gel cap or tablet 40 that has beenmodified by to render the gel cap pinched (thinner) at both ends 42 and44. The pinched or thinned ends 42, 44 are more than 0° and less than180° out of phase with respect to the longitudinal axis, i.e., 90° outof phase with respect to the longitudinal axis in this embodiment. Inthis embodiment, the middle section 46 (along the longitudinal axis) ofthe gel cap or tablet has a standard, e.g., generally cylindrical form.The modified gel cap or tablet 40 is asymmetric. Thus, FIGS. 4A-4C showan asymmetric oral dosage unit 40 that is asymmetric with respect to arotational axis RA in the center of the dosage unit, the rotational axisRA being perpendicular to a longitudinal axis of the dosage form.

FIG. 5A is a perspective view of still another embodiment an oral dosageunit of the present invention; and FIG. 5B is a cross-sectional viewalong lines 5B-5B of FIG. 5A.

FIGS. 5A and 5B show a “modified” gel cap or tablet 50 that has ridges52 running longitudinally on the periphery of the dosage unit 50. Theridges 52 and valleys between the ridges 52 reduce the contact patch ofthe dosage unit 50 with a flat surface compared to non-ridged dosageunit of the same size and shape. While the ridges 52 run longitudinallyon the periphery of the dosage unit 50 in this embodiment, the ridges 52need not run longitudinally but may be provided, e.g., concentrically orspirally as long as the ridges 52 reduce the contact patch of the dosageunit 50 with a flat surface compared to non-ridged dosage unit of thesame size and shape.

FIG. 6A is a top plan view of yet another embodiment of an oral dosageunit of the present invention; and FIG. 6B is a side elevation viewthereof (looking from an angle 90° from that of FIG. 4A and 90° fromthat of FIG. 6A). The oral dosage unit 60 shown in FIGS. 6A and 6B hasopposing outer major surfaces having convex dimples 62 so as to reducethe contact patch of the dosage unit 60 with a flat surface compared todosage unit of the same size and shape but without dimples. The dimplescan also be concave.

FIG. 7A is a perspective view of still another embodiment an oral dosageunit of the present invention; and FIG. 7B is a cross-sectional viewalong lines 7B-7B of FIG. 7A.

The oral dosage unit 70 of FIGS. 7A and 7B has a bulbous shape in whichone end 72 is enlarged with respect to another end 74. While this dosageunit 70 is symmetric about its longitudinal axis, it is asymmetric abouta rotational axis perpendicular to its longitudinal axis, so as toreduce the contact patch with respect to a flat surface; i.e., area 76will not come into contact with a flat surface.

As noted previously, the dosage form can be a in the shape of a sphere.Applicants have found that this shape reduces the contact patch with aflat surface. In one embodiment of the present invention, the spheredoes not have dimples, ridges and/or an annular ring. On the other hand,to reduce the propensity to roll on a flat surface and to further reducethe contact patch, other embodiments of the present invention mayinclude dimples, ridges and/or at least one annular ring provided on anouter surface of the spherical dosage unit.

FIG. 8A is a partially broken away plan view of yet another embodimentof the present invention showing a spherical oral dosage unit of thepresent invention. In FIG. 8A, the spherical oral dosage unit 80 a hasconvex dimples 82 provided on its outer surface.

FIG. 8B is a partially broken away plan view of yet another embodimentof the present invention showing a spherical oral dosage unit of thepresent invention containing a variation of the embodiment of FIG. 8A.In FIG. 8A, the spherical oral dosage unit 80 b has convex dimples 84provided on its outer surface.

FIG. 8C is a plan view of yet another embodiment of the presentinvention showing a spherical oral dosage unit of the present inventioncontaining a variation of the embodiments of FIGS. 8A and 8B. In FIG.8C, the spherical oral dosage unit 80 c has ridges 86 provided on itsouter surface.

FIG. 8D is a plan view of yet another embodiment of the presentinvention showing a spherical oral dosage unit of the present inventioncontaining a variation of the embodiments of FIGS. 8A, 8B and 8C. InFIG. 8D, the spherical oral dosage unit 80 d has an annular ring 88provided around its outer surface.

FIG. 8E is a plan view of yet another embodiment of the presentinvention showing a spherical oral dosage unit of the present inventioncontaining a variation of the embodiments of FIGS. 8A, 8B, 8C and 8D. InFIG. 8E, the spherical oral dosage unit 80 e has pair of annular rings88 provided around its outer surface and intersecting at 90° from eachother.

FIG. 9A is a top plan view of still another embodiment of an oral dosageunit of the present invention; FIG. 9B is a front elevation view thereof(looking from an angle 90° from that of FIG. 9A); and FIG. 9C is across-sectional view along lines 9C-9C of FIG. 9A. In the embodiment ofFIGS. 9A-9C, an oral dosage unit in a typical shape of a caplet 90 ismodified to have an annular ring 92 provided around its outer surface ata middle portion along its longitudinal axis.

FIG. 10A is a front elevational view of yet another embodiment of anoral dosage unit of the present invention; and FIG. 10B is a top planview thereof (looking at an angle 90° from that of FIG. 10A). In theembodiment of FIGS. 10A and 10B, an oral dosage unit in a typical shapeof a disc-shaped tablet (circular in plan view) 100 is modified to havean annular ring 102 provided around its outer surface at a centralportion.

While the annular ring is shown in FIGS. 8D, 8E, 9A-9C, 10A and 10Baround a middle portion of the dosage unit, the location is not limitedto the middle portion.

Viewed in another way, if, on a unidimensional flat surface, the contactmeasurement of a dosage form contact patch that is touching a flatsurface is 1 to 1 with a starting non-modified symmetrical dosage unit.as soon as one takes that dosage unit with the same total volume and 1)makes it asymmetric and/or 2) makes it ridged and/or dimpled and/or 3)uses a raised annular ring, then the ratio of the contact patch becomesless than 1 to 1 compared to the non-modified form of the same volumeand shaped (without the modification) dosage unit.

It is also possible to reduce the contact patch of a dosage unit with aflat surface, at least with respect to some orientations of the dosageform, by bending the dosage unit, either retaining its symmetry ormaking it asymmetric.

Of course, the present invention relates to dosage forms modified fromanother form and dosage forms originally manufactured in the modifiedshape.

FIG. 11A is a top plan view of one example of a die for forming oneexample of an oral dosage unit of the present invention and FIG. 11B isa cross-sectional view thereof along line 11B-11B of FIG. 11A. The die100 has top and bottom die halves 100 a, 100 b having respectivecavities that, in a closed state of the die, correspond to the shape ofa tablet of a shape corresponding to tablet 10 shown in, e.g., FIGS.1A-1C. The cavity is shown in dashed lines in FIG. 11A. The cavity inthe top portion 100 a includes cavity portions 112 a and 114 a; thecavity in the bottom portion 100 b includes cavity portions 112 b and114 b. As can be seen from FIGS. 11A and 11B, the die 100 can be used aswould be understood by those skilled in the art so that cavity portions112 a and 112 b form portion 12 of tablet 10 and cavity portions 114 aand 114 b form portion 14 of tablet 10.

FIG. 12A is a top plan view of one example of a die for forming anotherexample of an oral dosage unit of the present invention and FIG. 12B isa cross-sectional view thereof along line 12B-12B of FIG. 12A. The die400 has top and bottom die halves 400 a, 400 b having respectivecavities that, in a closed state of the die, correspond to the shape ofa tablet of a shape corresponding to tablet 40 shown in, e.g., FIGS.4A-4C. The cavity is shown in dashed lines in FIG. 12A. The cavity inthe top portion 400 a includes cavity portions 442 a, 444 a and 446 a;the cavity in the bottom portion 400 b includes cavity portions 442 b,444 b and 446 b. As can be seen from FIGS. 12A and 12B, the die 400 canbe used as would be understood by those skilled in the art so thatcavity portions 442 a and 442 b form portion 42 of tablet 40, cavityportions 444 a and 444 b form portion 44 of tablet 40, and cavityportions 446 a and 446 b form portion 46 of tablet 40.

FIG. 13A is a top plan view of one example of a die for forming yetanother example of an oral dosage unit of the present invention and FIG.13B is a cross-sectional view thereof along line 13B-13B of FIG. 13A.The die 900 has top and bottom die halves 900 a, 900 b having respectivecavities that, in a closed state of the die, correspond to the shape ofa tablet of a shape corresponding to tablet 90 shown in, e.g., FIGS.9A-9C. The cavity is shown in dashed lines in FIG. 13A. The cavity inthe top and bottom portions 900 a, 900 b include respective cavityportions 920 a, and 920 b. As can be seen from FIGS. 13A and 13B, thedie 900 can be used as would be understood by those skilled in the artso that cavity portions 920 a and 920 b form portion 92 of tablet 90.

FIG. 14 is graphic representation of the average esophageal transittimes (plotted in the vertical access) of four different tablet shapes,Control (a standard oblong pill shape), Lines (modeled on FIG. 5),Saturn (modeled on FIG. 9), and Helicoptor (modeled on FIG. 3). The invivo work yielding these plotted results is described in Example G.

The die shapes shown in FIGS. 11A, 11B, 12A, 12B, 13A and 13B areexamples only, and, as would be understood by those skilled in the art,other die shapes can be used to form other examples of the dosage unitsof the present invention.

As is known to those skilled in the art, two-piece telescoping gelatinor vegetable capsule can be made in two parts by dipping metal rods inthe gelling agent solution. In making standard capsule shapes, the rodis merely lifted from the solution and capsule part shed from the metalrod. On the other hand, in making capsules having some of the shapes,e.g., asymmetric shapes, of the present invention (for example theshapes of FIGS. 1A-1C, 2A-2 c, 4A-4C, etc.), the capsule part cannot besimply shed from the shaped rod or die, since an end of the shaped rodor die may be wider than the opening of the formed capsule part to beshed. Therefore, contrary to the present state of the art, it would benecessary to use a shaped rod or die the wide portion of which iscollapsible so that it the capsule part can be shed therefrom. That is,the die for forming such a dipped capsule around a capsule-formingregion thereof includes a region adjacent an end of the capsule formingregion that is wider than another portion of the capsule forming regionand which can collapse so that the die can shed the formed capsulefragment by removing the die through a neck of the capsule fragment thathas a smaller diameter than the width of the region adjacent an end ofthe capsule forming region.

The following examples demonstrate the advantageous effects of thepresent invention. However, the present invention is not limited to thefollowing examples or to the embodiments shown in the drawings.

EXAMPLE A

The following materials were used: Right-Aid brand Ibuprofen gel caps,Scotch brand “Super Strength” packing tape and a slide lock adjustablepliers.

The experiment was fashioned to use the tape as an adhesive surface. Thetape was placed at angle thirty three degrees from horizontal include toform an approximately ten inch long ramp. Gel caps—modified andunmodified controls—where placed side by side on the ramp and 20 cc ofroom temperature water were poured behind the gel caps to determine theability of the 20 cc of water to dislodge the gel caps from the tape.

The “modified” gel cap was modified by using the pliers on the end ofthe gel cap so as to render the gel cap pinched (thinner) at the farside. Care was taken to avoid puncture of the gel cap. While a number ofgel caps where punctured during practice, after some practice, it becamepossible to manipulate the end of the gel cap using the pliers withoutpuncture. The “modified” gel cap had a shape similar to that shown inFIGS. 1A-1C.

The result of the pinching was to render the gel cap asymmetric on anyrotational axis.

The asymmetric gel cap was placed on the ramp (pinched side downgrade)along side of an unmodified gel cap. The 20 cc of water was then pouredbehind the two gel caps. The asymmetric gel cap was washed off the taperamp; the unmodified control remained adhered to the tape ramp withoutmoving.

This experiment was repeated with the pinched side upgrade, again usingthe unmodified control and 20 cc of water. The result was the same; theasymmetric gel cap was washed off the tape ramp. The unmodified controlremained adhered to the tape ramp without moving.

For the purposes of accuracy, each iteration of this experiment wasrepeated five times—each time with the same results.

It was concluded that the reduction of the contact patch effected by thepinching of the gel cap was responsible for the improved performance ofthe modified, pinched gel cap over the control.

EXAMPLE B

It was decided to carry out a different test from that of Example A. Inthis test, 10 CC of water were placed into a pyrex beaker. The sampletablets were added to a dry pyrex beaker; the water was added and thenslowly expelled. The purpose was to see which tablets were expelled withthe water (and which were not). A tablet expelled from the beaker was a“pass.” A tablet retained in the beaker was a “fail.”

The first control (Tablet 1) was a 200 mg Care One Ibuprofen. The secondtablet (Tablet 2) was fashioned from modeling clay to mimic the size andshape of Tablet 1, so as to observe any differences caused by the use ofmodeling clay. The third tablet (Tablet 3) was made by taking tabletslike Tablet 2 and pinching one end concave (similar to the shape shownin FIGS. 2A-2C). The second control (Tablet 4) was a 220 mg Aleve LiquidGel. The fifth tablet (Tablet 5) was made from modeling clay to mimicthe size and shape of Tablet 4. The sixth tablet (Tablet 6) was made bytaking samples of Tablet 5, and pinching one end (resulting in a concaveimpression) (similar to the shape shown in FIGS. 2A-2C). The seventhtablet (Tablet 7) was made by pinching both ends (resulting in concaveimpressions) and then rotating the middle of the tablet by 90 degrees(similar to the shape shown in FIGS. 3A-3C). The third control (Tablet8) was Good Sense Ibuprofen liquid gels (200 mg).

Five fresh samples of each of the above were used in order to performfive iterations of the experiment with the following results:

Pass Fail Tablet # (expelled from beaker) (retained in beaker) Tablet 10 5 Tablet 2 1 4 Tablet 3 4 1 Tablet 4 0 5 Tablet 5 1 4 Tablet 6 5 0Tablet 7 5 0 Tablet 8 0 5

The slightly improved performance of Tablet 2 over Tablet 1 wasattributed to the surface properties—gel caps can be tacky and stick.The reduction of the contact patch size through the use of asymmetricshapes greatly enhanced the propensity of the dosage form to transit.

EXAMPLE C

The intention of Example C was to re-test crimped soft gels similar tothe shape tested in Example A but in this case employing a testingmethod more similar to that of Example B.

Using an adjustable wrench and Good Sense® 200 mg Ibuprofen LiquidSoftgels, we crimped one end of the Softgels to an approximate length of3/16's of an inch at the crimped end. The testing procedure of Example Bwas performed approximately thirty minutes after the Softgels werecrimped. The results were as follows:

Unmodified Good Sense ® Crimped Good Sense ® Liquid Softgel LigquidSoftgel Fail Pass Fail Pass Fail Fail Fail Pass Fail Pass Pass Pass FailFail Implies pass/fail rate of 14.3% Implies pass/fail rate of 71.4%

Again, the reduction of the contact patch through the introduction ofasymmetry to the shape resulted in an enhanced propensity to transit.

EXAMPLE D

Example D again uses the methodology of Example B but in this caseapplied to a modified existing liquid gel that was crimped at both endsand then twisted 90 degrees (similar to the shape shown in FIGS. 4A-4C).

We used Aleve® Liquid Gels (220 mg). Using an adjustable wrench, bothends were crimped. Following crimping of each end, the double crimpedLiquid Gel was twisted by 90 degrees.

Aleve ® with ends crimped and twisted Unmodified Aleve ® 90 degrees FailPass Fail Pass Fail Pass Fail Pass Fail Pass 0% Pass rate 100% pass rate

This example again demonstrated that the introduction of asymmetryserved to increase transit propensity—here in dramatic fashion over thecontrol.

EXAMPLE E

Again using modeling clay and in some cases a washer (in which the claywas molded around the washer to increase density), sample tablets weremade and tested in accordance with the water evacuation method ofExample B.

We tested four designs. The first design was initially shaped akin tothe Good Sense® 200 mg Ibuprofen tablet. As an added feature to reducecontact surface, ridges were added all around the dosage form, runninglengthwise (similar to the shape shown in FIGS. 5A and 5B).

The second design was initially shaped akin to the Aleve® liquid gel.Again, like the previous design, we added ridges running lengthwise tothe design (similar to the shape shown in FIGS. 5A and 5B).

The third design was a round disc-shaped tablet built around a washer toincrease density. Dimples were created on the two flat sides of thisdesign. The dimples were raised approximately 1-2 mm from the flatportion (similar to the shape shown in FIGS. 6A and 6B).

The fourth design was shaped identically to the third design but it wasmade solely from clay and thus had a lower density. Again, the dimpleswere raised approximately 1-2 mm from the flat portion (similar to theshape shown in FIGS. 6A and 6B).

As before, we tested five samples of each design.

Mass of Sample Pass Fail First Design (ridged ibuprofen shape) Sampleone .35 g Pass Sample two .35 g Pass Sample three .38 g Pass Sample four.38 g Pass Sample five .38 g Pass Second Design (ridged Aleve ® shape)Sample one .37 g Pass Sample two .34 g Pass Sample three .35 g PassSample four .35 g Pass Sample five .35 g Pass Third Design (weighteddimpled disc) Sample one .76 g Pass Sample two .61 g Pass Sample three.76 g Pass Sample four .77 g Pass Sample five .64 g Pass Fourth Design(unweighted dimpled disc) Sample one .33 Pass Sample two .36 Pass Samplethree .34 Pass Sample four .36 Pass Sample five .34 Pass

The four designs in this example showed the efficacy of dimples andridges in reducing surface contact area, thereby reducing adhesion areaand promoting effective transit. The absence of any measured differencebetween designs three and four—of the same design with differentdensities—created the desire for further study of the role of density intransit.

The embodiments and examples of the invention have been described indetail above, but the invention may include various modificationswithout departing from the spirit and scope of the invention.

EXAMPLE F

This example used, as a control, CVS brand 81 mg Aspirin (enteric coatedtablets). Each control tablet had a mass of 0.2 grams. Using low densitymodeling clay, tablets were made in the same shape as the control with amass of 0.063 grams.

The tablets were tested in a glass container with ¼ cup of roomtemperature water as follows. The tablet was added to a pre-wettedcontainer. ¼ cup of water was added. The container was immediatelyinverted. If the sample evacuated, a pass was recorded. If the tabletadhered a fail was recorded. Ten samples of each of the control and lowdensity model were tried with results as follows:

Number Control Low Density Sampole 1 Fail Pass 2 Fail Pass 3 Fail Pass 4Fail Pass 5 Fail Pass 6 Fail Pass 7 Fail Pass 8 Fail Pass 9 Fail Pass 10Fail PassThese results suggest that the increased buoyancy associated with lowerdensity tablets enhanced transit—despite the testing method of invertingthe beaker (thereby exerting greater gravitational pull on the moredense, control). This suggests a strong benefit to the buoyant samplewhereby the increased buoyancy retards the formation of adhesionaryforces.

EXAMPLE G

It was considered valuable to perform in vivo studies of the effect oftablet design on esophageal transit in order to determine theapplicability of the in vitro testing described herein. One of thedifficulties in this lightly studied area is that there are noestablished, or even suggested in vitro methods to model transit. Thus,the inventor is left to his own devices.

As concerns in vivo study, however, we are fortunate that study ofesophageal transit is understood (see the references cited above).

Four pills were prepared for this study. The excipients included:dibasic calcium phosphate more starch and in the center, a magneticmarker of cylindrical shape: diameter 3 mm and height 4 mm; they werenamed Control (modeled on tablet 1 of Example B), Lines (modeled on FIG.5), Saturn (modeled on FIG. 9) and Helicopter (modeled on FIG. 3). Theirsize was around 20 mm of length and all they have the same weight.

For this study, 21 subjects, males and females, were enrolled: i) agefrom 17 to 55 years, ii) weight from 52 to 120 kg, iii) height from 1.59to 1.77 m and iv) body mass index variation from 17.96 to 43.03 kg/m².

Three magnetic sensors (MS) were used in order to register the pass ofeach pill through the esophagus: First MS was on the top end of thesternum, next to supra sterna artery; Second MS was 12.5 cm, over theesophagus, from the first one; Third MS was next to Xiphoid process, to12.5 cm from the second one.

The average esophagus length was 25cm. This distance was the same foreach subject.

SUBJECT POSITION: In semi-Fowler's position, in this case, each patientwas lying in bed in a supine position with the head of the bed at 25degrees.

Data acquisition was performed in LabVIEW platform at rate frequency of30 samples per second. This file was exported to Matlab platform whereit was plotted.

Descriptive statistical was used in order to identify the esophagealtransit time.

The Control: mean=16.86, std=12.04 seconds Variations from minimum tomaximum (3.6 to 35.9) seconds.

The Lines: mean=6.44, std=3.81 seconds Variations from minimum tomaximum (3 to 12) seconds.

The Saturn: mean=3.04, std=1.35 seconds Variations from minimum tomaximum (1.22 to 4.2) seconds.

The Helicopter: mean=1.78, std=1.33 seconds Variations from minimum tomaximum (0.3 to 5.17) seconds.

This is an average of a whole each group. These results are graphicallyshown in FIG. 14.

An average of the whole each group is also shown. In order to see theself variation of each subject was divided in esophageal transit time ofhis own control, then the descriptive statistical is performed, mean andstandard deviations are computed: Control: 100%; Lines: 80%; Saturn:45%; Helicopter: 18%.

No significant difference was observed by gender, age or weight.

Clear improvements in transit from the control pill to Saturn andHelicopter pills were observed. Some improvement in transit time wasobserved for the Lines model, even though it is likely that the Linesmodel was not created with sufficiently deep or properly spaced ridgesand valleys so as to further reduce the improvement when compared withthe Control. We believe that with modification of the foregoing, theperformance of the Lines model would be improved.

This study makes clear that the contact patch reduction does in factmake a substantial clinical difference. These studies, with controls,show consistent objective results that are well beyond any question ofeffectiveness. Furthermore when an additive feature, such as lowereddensity/added buoyancy is added to this design, it is obvious that theresults would be additive.

By the use of a reduced contact patch, the dosage unit of the presentinvention makes the esophageal transit of a drug possible regardless ofbody position. Thus, the present invention allows for the altering ofadministration instructions for existing medications. For example, withimproved transit, the instruction of FOSAMAX® for the patient to remainstanding for one hour after administration can be relaxed or even doneaway with in its entirety.

Two or more of the various embodiments may be combined, with or withouta density reduction, to obtain a reduced contact patch. For example, anyor all of asymmetry, annular ring, grooves, concavities and convexitiesmay be combined in one dosage unit, with or without a density reduction.

As will be apparent to those skilled in the art, various modificationsof the disclosed embodiments and examples can be made without departingfrom the teachings of the present invention.

We claim:
 1. An oral dosage unit containing a bioactive, in which anouter surface of the dosage unit is ridged and valleyed so as to reducethe contact patch of the dosage unit with a flat surface compared tonon-ridged dosage unit of the same size and shape.
 2. The oral dosageunit according to claim 1, wherein the dosage unit is a gel cap, theouter surface of which is ridged and valleyed.
 3. The oral dosage unitaccording to claim 2, wherein the ridges and valleys between the ridgesextend longitudinally on the periphery of the dosage unit.
 4. The oraldosage unit according to claim 2, wherein the ridges and valleys betweenthe ridges extend concentrically or spirally around the periphery of thedosage unit.
 5. The oral dosage unit according to claim 1, wherein thedosage unit is a tablet, the outer surface of which is ridged andvalleyed.
 6. The oral dosage unit according to claim 5, wherein theridges and valleys between the ridges extend longitudinally on theperiphery of the dosage unit.
 7. The oral dosage unit according to claim5, wherein the ridges and valleys between the ridges extendconcentrically or spirally around the periphery of the dosage unit. 8.The oral dosage unit according to claim 1, wherein the dosage unit has aspherical shape, the outer surface of which is ridged and valleyed. 9.An asymmetric oral dosage unit containing a bioactive, the dosage unitbeing asymmetric with respect to a rotational axis perpendicular to alongitudinal axis of the dosage form, the rotational axis being locatedsubstantially at a mid point along the longitudinal axis, wherein anouter surface of the dosage unit is ridged so as to reduce the contactpatch of the dosage unit with a flat surface compared to non-ridgeddosage unit of the same size and shape.